The overall goal of this proposal is to define mechanisms of neuronal injury following focal and global cerebral ischemia in adult and pediatric animals. The Program represents a multidisciplinary mechanistic approach involving interactive productive investigators with complimentary areas of expertise who have long been committed to studies of the cerebral circulation and ischemia. One major aim will be to integrate the activities of various disciplines such that the interrelationships will result in a greater scientific contribution than could be achieved than if each project were pursued individually. The major theme is that state-of-the-art molecular, genetic, cellular, neuropathologic, physiologic, and neurobehavioral approaches are proposed to examine the mechanisms of neuronal injury and neuroprotection from stroke and cardiac arrest/CPR (focal and global cerebral ischemia). We will determine the neuroprotective mechanisms associated with sigma receptor signaling, sex hormones, nitric oxide, antioxidants, and poly (ADP-ribose) polymerase (PARP). The Program has several important strengths: First, the investigators have a long history of interactive studies of the brain and its vasculature under normal and pathophysiologic conditions. Second,-preliminary data in each project indicate feasibility of our approaches and demonstrate evidence of integration of the old and new parts of the Program. Third, the investigators are leaders in the field concerning mechanisms of neuronal injury, cerebrovascular regulation, ischemia, and neuroprotection. Fourth, the investigators use sophisticated physiological approaches and molecular, genetic, cellular, neuropathological and neurobehavioral approaches which have been incorporated to facilitate novel insight into neuronal injury and neuroprotection. The Program consists of 4 projects: 1) Sigma receptor signaling in focal cerebral ischemia; 2) Gender differences in stroke; 3) PARP in cardiac arrest/CPR; and 4) Cardiac arrest/CPR - mechanisms of brain injury in the newborn. This program is supported by 3 Core facilities: 1) Administration; 2) Cells and Tissues-Culture and Neuropathology; and 3) Transgenic Animals.